The invention relates to antiviral pharmaceuticals, and more particularly relates to antiviral pharmaceuticals for topical administration. In its most immediate sense, the invention relates to pharmaceuticals for treating patients with anogenital warts.
Ranpirnase is a protein with ribonuclease activity, it has a molecular weight of approximately 12,000 Daltons, and it has an amino acid sequence disclosed and claimed in U.S. Pat. No. 5,559,212. It can be isolated from embryos and eggs of the Rana pipiens frog or produced as a recombinant protein (see e.g. U.S. Pat. No. 6,175,003 B1). Commonly-owned U.S. Pat. No. 8,663,964 B2 teaches that ranpirnase and another enzymatically-active ribonuclease are active against human papillomavirus (hereinafter, “HPV”) and that HPV can be treated by using either of these two ribonucleases on an HPV-infected region of a patient. Anogenital warts are caused by various human papillomaviruses, and no satisfactory treatment exists for this sexually-transmitted disease since all available treatment modalities target the lesions and lack viricidal activity against HPV.
It has been proposed to treat anogenital warts intralesionally, i.e. by injecting an active pharmaceutical ingredient (“API”) into the wart to be treated. In many situations—where the warts are small or too numerous, or in locations where an injection would be too painful—this would be unsatisfactory.
It has also been proposed to treat anogenital warts topically. Because the HPV-infected cells are located beneath the surface of the patient's skin and would not be directly contacted by the API, this proposal assumed that it would be necessary to administer the API using a special vehicle that would penetrate through the intervening layers of the patient's skin to thereby deliver the API to a location where its anti-HPV activity would be useful.
A Phase I compassionate use observational study was carried out in Argentina on male volunteers with anogenital warts. Commonly-owned parent patent application Ser. No. 14/462,520 filed Aug. 18, 2014 discloses an unexpected and surprising result from this study, namely, that it is unnecessary to administer the API using a vehicle that would penetrate through the layers of the patient's skin. Rather, that study demonstrated that topical ranpirnase therapy for HPV did not—as was expected—require a vehicle having penetrating characteristics. Rather, it appeared that the vehicle need only not unacceptably interfere with the enzymatic activity of ranpirnase. Furthermore, because there are other enzymatically-active ribonucleases that behave similarly to ranpirnase, the referenced parent patent application stated that it was reasonable to expect that any such ribonuclease would, when combined with a suitable vehicle, have an activity similar to that of ranpirnase.
This Phase I study has now been completed, with most favorable results. While the study lasted for only eight weeks, in more than 80% of the evaluable patients no warts were visible, i.e. those patients appeared to be “clinically healed”. To a person of ordinary skill in the art, this is strong evidence that the invention is reasonably correlated with usefulness in treating HPV.
Significantly, it is believed that the vehicle need not be entirely free of anti-enzymatic activity. In some instances, it is believed possible to overcome anti-enzymatic qualities of the carrier by increasing the concentration of the enzymatically-active ribonuclease.
In accordance with the invention, a pharmaceutical comprises a therapeutically effective quantity of an enzymatically-active ribonuclease and a vehicle that does not unacceptably interfere with such enzymatic activity.
Preferred embodiments of the invention use ranpirnase as the enzymatically-active ribonuclease. While an oil in water-based vehicle containing other components such as collagen can be used, preferred embodiments use an aqueous vehicle. Preferred aqueous vehicles are gels, serums, lotions, or approved sexual lubricants (which may themselves be gels or lotions). This is because gels, lotions, serums, and sexual lubricants are viscous or can be made viscous so that the invention will remain where it has been applied and will not run off. Advantageously, and in accordance with preferred embodiments of the invention, the pharmaceutical has between 1 and 3 mg of ranpirnase per ml of vehicle.